New ALS Research from the American Academy of Neurology Meeting

May 18, 2016

Some important advances in understanding and treatment of ALS were reported at the Annual Meeting of the American Academy of Neurology, held in Vancouver, BC, in April. Among the highlights were studies conducted by Drs. Lindsey Hayes, Sara van Mossevelde, Adriano Chio, Teresa Jacobs, Jeremy Shefner and Wendy Kaye.

Lindsey Hayes, M.D., Ph.D., from Johns Hopkins University in Baltimore, presented evidence that tracking one of the unusual proteins made by the C9orf72 mutation may provide a good biomarker for response to therapy against the mutation. Among other effects, the mutation causes the production of so-called dipeptide repeat proteins (DPRs), small proteins composed of two repeating amino acids. Dr. Hayes found that the level of one DPR, made of glycine and proline, fell in step with a dose increase of an antisense treatment against the C9orf72 mutation, suggesting that measurement of this DPR may be useful in clinical trials of antisense treatment. The work was done in cell culture and will need to be validated in other models before relying on it for clinical trials.

Sara van Mossevelde, M.D., of University of Antwerp in Antwerpen, Belgium, presented evidence that the C9orf72 gene mutation, the most common genetic cause of ALS, exhibits a phenomenon known as “anticipation,” meaning that the disease begins earlier in each succeeding generation, often due to expansion of a repeat mutation over time. She and her colleagues studied the clinical characteristics of 29 multi-generational families with the mutation and showed that those in the youngest generation had disease onset about 7 years earlier than their grandparents. Perhaps surprisingly, the duration of disease did not differ between the generations, unlike the common pattern of more severe disease in successive generations seen in other diseases that show anticipation. The explanation for this difference is not yet clear.

Dr. van Mossevelde provided important new clinical features of people living with ALS due to mutations in the TBK1 gene. The mutation also causes frontotemporal dementia (FTD). Onset was about age 62 and the average disease duration was 4.7 years. Behavioral changes and memory loss were important features of those with FTD.

Adriano Chio, M.D., of University of Torino in Turin, Italy, presented data on the influence of the APOE gene on the cognitive features of people with ALS. The same gene figures prominently in Alzheimer’s disease, where possession of the APOE2 allele (form of the gene) is associated with a reduced risk of dementia. Surprisingly, Dr. Chio found the opposite in ALS. People with ALS carrying the APOE2 allele had a 2.5-fold increase in their risk for dementia, compared to those not carrying the allele. The reason for this difference between ALS and Alzheimer’s disease is unclear, but investigation of the reason may provide some insight into the factors that determine whether a person with ALS will develop dementia.

Commencing non-invasive ventilation (NIV) before it is needed may provide some additional benefits compared to waiting, according to a pilot study from Teresa Jacobs, M.D., and colleagues at the University of Michigan in Ann Arbor, Mich. Using a novel trial design, in which people with ALS whose forced vital capacity (FVC), a standard measure of respiratory function, was above 50% of predicted, were randomized to either active NIV or sham NIV, in which the settings on the ventilator were too low to deliver the appropriate force for ventilatory assistance. The FVC of those receiving active treatment declined more slowly than it did in those receiving sham treatment. “This trend toward improved respiratory function seen in this pilot trial warrants further study of early NIV therapy in ALS,” Dr. Jacobs concluded.

Jeremy Shefner, M.D., Ph.D., of Barrow Neurologic Institute in Phoenix, Ariz. and colleagues presented data showing that changes in a respiratory measure called slow vital capacity (SVC) predicted changes in other measures of ALS decline, including need for invasive ventilation and risk of death. The results are important for interpreting clinical trial results for tirasemtiv, a drug shown to slow the decline in SVC in people with ALS. A Phase III clinical trial to test tirasemtiv, called VITALITY-ALS (Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year-ALS) began in July 2015, in which change in SVC will be a primary outcome measure to determine the drug’s symptomatic effect in ALS.

Wendy Kaye, Ph.D., and colleagues from the National ALS Registry showed the feasibility of a national biorepository of ALS biospecimens, including tissue and body fluids. Based on the success of this pilot study, the Registry will launch a nationwide biorepository in the fall of 2016.